Stable isoproteronol compositions



United States Patent 3,039,929 STABLE ISOPROTERONOL COMPOSITIONS George L. Stanko, Waukegan, 111., assignor to Abbott Laboratories, North Chicago, 111., a corporation of Illinois No Drawing. Filed Mar. 17, 1960, Ser. No. 15,549 Claims. (Cl. 167-65) This invention relates to novel compositions containing the well-known bronchodilator, isoproteronol. In particular, this invention is concerned with composition forms wherein said isoproteronol is maintained in stable form over extended periods of time.

Isoproteronol has been known to the art for many years as a useful bronchodilator or a medicament of particular applicability to the treatment of asthma. Isoproteronol is identified by the chemical name, oz-(iSO- propylaminomethyl)protocatechuyl alcohol. This foregoing bronchodilator is most usefully employed to relieve bronchiol constrictions and has attained widespread use and high popularity both among physicians and distressed patients. The beneficial properties of this active ingredient do not reside in permanent relief or cure of the etfiiction, but in temporary relief; consequently, the asthmatic must repeatedly administer isoproteronol to himself during the periods of demand.

It can be seen from the foregoing discussion that a composition form is desired which is readily and conveniently administered to the distressed subject. One of the means used to administer this beneficial medicament has been a mechanical inhalator. The mechanical inhalator is a closed body section having an open end which is designed to be placed in the mouth of the patient. The body section, at the other extremity, has a constricted portion which separates a substantially bulbar-shaped body from the remaining body section. Proximate to the constricted portion is a cartridge which contains isoproteronol. In the bulbar-shaped body there is a small weight which can be placed in motion by the suction created from inhalation by the patient. The patient places the open end of the apparatus in his mouth, inhales forcibly and causes the small weight to move and strike the cartridge, thereby shaking loose the isoproteronol therefrom. It is apparent that this method of administering isoproteronol has many disadvantages, among which can be numbered inefficient introduction of the active ingredient to the bronchiols, aggravated physical stress on an already distressed patient and general awkwardness in handling and manipulation.

The self-propellant inhalators or aerosols have also been used to administer isoproteronol. Such embodiments require the use of liquid-compressed gases, such as those known in the art as fluorinated hydrocarbons (Freons), to expel the active ingredient in small particle size. Such particular embodiments would be highly desira-ble, but prior hereto, the isoproteronol was not maintained in sustained stability in the mixed alcohol solution and liquid-compressed gas fluorinated hydrocarbons.

An object of this invention is to provide composition forms wherein isoproteronol is maintained in stable form for extended periods of time.

Another object of this invention is to provide such stable compositions in forms which are elficiently administered and pleasingly accepted.

Still another object of this invention is to provide a useful, self-propellent pharmaceutical form which utilizes compressed-liquid gases to expel isoproteronol in stable form.

It is yet another object of this invention to provide an aerosol mixture wherein isoproteronol is present and retained in stable form.

In the accomplishment of the foregoing objects and in accordance with the teachings of this invention, it is now provided that aerosol mixtures can be prepared for use in self-propellent embodiments wherein the isoproteronol is maintained in stable form in a mixture of alcohol and compressed-liquid gas fluorinated hydrocarbons by the presence of small amounts of ascorbyl palmitate.

Aerosol compositions of isoproteronol require that said active ingredient be dissolved in an alcohol vehicle because such alcohol vehicles are miscible vw'th various liquid, compressed-gas, fluorinated hydrocarbons. Such fluorinated hydrocarbon liquids are commercialy known as various Freons, lsotron, Genetron and by other names. These foregoing gas propellents are particularly useful for aerosol compositions wherein the active medicament must be expelled in small particle size. However, as stated hereinbefore, the active ingredient in such aerosol mixtures must be portected against degradation. It is now provided that this agent is ascorbyl palmitate. It is known that ascorbic acid is an antioxidant, but ascorbic acid is non-operable for the foregoing aerosol mixtures because it is incompatible therein. The ascorbic acid comes out of alcohol solution in the presence of the foregoing fluorinated hydrocarbon liquid gases and, thereafter, the isoproteronol quickly succumbs to the deteriorating elements. The ascorbyl palmitate has been surprisingly and unexpectedly found not to possess this disadvantage.

It is provided by this invention that ascorbyl palmitate is peculiarly operable for the aerosol mixtures, but that the inherent properties of ascorbic acid are beneficial for stabilizing isoproteronol. Such beneficial properties are unique because many other antioxidants that are known to the art are inoperable for stabilizing and protecting isoproteronol. Among other antioxidants which have been found undesirable are butylated hydroxy anisole, propyl gallate, nor-dihydroguaretic acid, sodium metabisulfite, ethyl hydrocafieate, di-tert-butylparacresol and others.

The advantages of this invention are realized by incorporating at least about 0.05% Weight per volume of ascorbyl palmitate in the areosol mixture. A useul and preferred concentration of the ascorbyl palmitate is about 0.5% weight per volume in the aerosol mixture; but it should be understood that once the prescribed minimum concentration is exceeded, continual increases will not deleteriously affect the accomplishments of this invention. The upper limits of the ascorbyl palmitate concentration will be determined by the obvious reluctance of the practitioner to add amounts in addition to that amount which accomplishes the desired object. An operative and practical range comprises from about 0.1% to about 0.25% weight per volume of ascorbyl palmitate in the finished aerosol mixture.

The aerosol mixture will contain a therapeutic amount of isoproteronol HCl which amount can be selected from the range of about 0.1% to about 0.3% weight per volume in the finished aerosol mixture. Such amounts of active ingredient will be stabilized by the ascorbyl palmitate as described supra. It has been additionally found that a particular salt form of isoproteronol may be an incompatible element of the aerosol mixture, e.g., isoproteronol sulfate will come out of the aerosol mixture. Isoproteronol hydrochloride has been found to be compatible and useful for the aerosol mixtures described herein.

The foregoing and following description and disclosure of the aerosol compositions makes use of the terms alcohol solution, fiuorinated hydrocarbons and aero sol mixture. The term alcohol solution shall mean a substantially anhydrous alcohol such as ethanol which has dissolved therein the isoproteronol and the ascorbyl palmitate. The fluorinated hydrocarbons shall mean al- 3 kanes of 1-2 carbons with fiuoro or bothchloro and fiuoro groups attached thereto. Such fluorinated hydrocarbons are known commercially as Freons and among such Freons which are gainfully adapted to aerosol compositions are Freon 11 (trichloromonofluoromethane), Freon 12 (dichlorodifluoromethane), Freon 11'3 (monochlorotrifluoromethane), Freon 21 (dichloromonofluoromethane) and Freon 114 (dichlorotetrafiuoroethane). The amount of any particular fluorinated hydrocarbon or the selection of any particular mixture of fluorinated hydrocarbon gases will be determined by the gauge pressures desired for the aerosol container. Reference may be made to US. 2,868,691 wherein a more detailed discussion of the various Freons and their properties in aerosol may be found. The type of aerosol container, the type of valves crimped thereon and the method of filling such containers may be ascertained by reference to wellknown portions of the art dealing with this subject. Among such references may be mentioned the foregoing US. 2,868,691; U.S. 2,728,495; U.S. 2,721,010; Aerosol Age, volume 2, No. 9, page 191?, page 33ft, page 44ft (September 1957), and other works available to the art.

Aerosol mixtures" shall mean a mixture of the alcohol solution and the fluorinated hydrocarbon or hydrocarbons. A further feature of this invention provides that the alcohol solution and fluorinated hydrocarbon or hydrocarbons shall be combined in substantially a 1:1 volume ratio, or 50% volume per volume of both the fiuorinated hydrocarbon and the alcohol solution. This allows the surprising and unexpected stabilization effects of theascorbyl palmitate to operate. It has been found that substantial departures from this ratio will result in a haze or precipitate in the aerosol mixture. The volume per volume units are meant to represent their usual pharmaceutical meaning. Thus, in a 10 ml. volume of aerosol mixture, 50% volume per volume of alcohol solution means that ml. of said alcohol solution is present therein.

In an alternative aerosol mixture, a small amount of water in the range of about 1% may be present in order to place the active ingredient more quickly into solution. The ascorbyl palmitate is dissolved in the alcohol portion of the composition, but provides its beneficial effects in stabilizing isoproteronol, despite the small presence of water. It is to be remembered that this small amount of water will not hamper the'excellent stabilization of isoproteronol with ascorbyl palmitate in alcohol to solutions.

The following examples are presented to illustrate various embodiments of the invention. It is understood that such examples do not represent and are not intended to represent exclusive embodiments; such examples serve merely to illustrate the practice of this invention.

EXAMPLE I and 500 cc. of the liquid, compressed-gas, fluorinated hydrocarbons. The aerosol mixture is then said to contain 50% volume per volume of the alcohol solution and 50% volume per volume of the fluorinated hydrocarbons. Samples of this aerosol mixture are then placed in aerosol containers at a temperature of about 20 F. by placing in each container 10-11 gms. of the aerosol mixture and then crimping on each container a suitable release valve mechanism. The finished aerosol mixture is compounded to contain 0.25% of isoproteronol hydrochloride, 0.2% of ascorbyl palmitate and 0.5% water.

The stability of isoproteronol in both the alcohol solution and the aerosol mixture is evaluated by the method of photofluorescence as determined with the aid of an Amico-Bowman Spectrophotofluorometer. This apparatus fluoresces the active material at a particular wavelength of ultra-violet light. Only the undegraded isoproteronol fluoresces at that particular ultra-violet wave- The solution was prepared according to the procedures set forth in Example I. The finished aerosol mixture is compounded to contain 0.25% of isoproteronol HCl, 0.2% of ascorbyl palmitate and 0.5% water. The initial alcohol solution assay showed an isoproteronol content of 5.83 mg./ml. or 116.6% of theory. After three months at room temperature, the isoproteronol content was 5.80 mg./ml. or 116.0% of theory. A sample that stood at room temperature for one year was assayed and found to contain 5.7 mg. of isoproteronol per ml. or 114% of theory.

ALCOHOL SOLUTION The following examples employ the same process steps of preparation and are presented to teach operable vari- Percent Ingredient Amount ations in the practice of the invention.

EXAMPLE III 150 roteronol H drochloride 2 5 gins g y Palmtyate 2'0 gms A. ALCOHOL SOLUTION Distilled Water Ethyl Alcohol (200 Proof) Percent Ingredient Amount FLUORINATED HYDROCARBONS 0.4 Isoproteronol Hydrochloride 20 mg. 0.2 Ascorbyl Palmitate 10 mg. Ethyl Alcohol (200 Proof), q.s 5 cc. 15 Dichlorodifiuoromethane (Freon 12) 112.0 ms. 85 Dichlorotetrafiuoroethane (Freon 114)-.. 680.0 gms.

B. FLUORINATED HYDROCARBONS The medicament is moistened with water and added to 15 Dichlomdmuommethane (Freon 12) 1 12 gms the alcohol followed by addition of ascorbyl palmitate. 85111111111111 Dichlorotetratluoroethane (Freon 115:: 6180 gins: Both the foregoing alcohol solution and the fluorinated hydrocarbons are cooled to about 20 F. by means of refrigeration equipment and are then mixed. The combined volume of the mixture is about 1000 cc. which consists substantially of 500 cc. of the alcohol solution The foregoing formulation results in an aerosol mixture having a volume of 10 cc. wherein the isoproteronol hydrochloride has a final concentration of .2%, and the ascorbyl palmitate has a final concentration of .1%.

Percent Ingredient Amount Isoproteronol Hydrochloride 10 mg. Ascorbyl Palmltate 10 mg. Distilled Water 250 mg Ethyl Alcohol (200 Proof), q.s cc.

B. FLUORINATED HYDROCARB ONS Dichlorodifluoromethane (Freon 12) 1.12 gms. Dichlorotetrafluoroethane (Freon 114).-. 6.80 gins.

The final aerosol mixture has a concentration of cc., and the isoproteronol hydrochloride is present therein in a concentration of .l% and the ascorbyl palmitate is also present therein in a concentration of .l%.

EXAMPLE V A. ALCOHOL SOLUTION 'Ihe final aerosol mixture contains a volume of 10 cc. in which the isoproteronol hydrochloride is present in a concentration of .25 and the ascorbyl palmitate is present in a concentration of .1%.

In the following examples various embodiments are presented wherein individual or mixed fluorinated hydrocarbons are variously compounded in the aerosol mixture. In each of the following examples the alcohol solution listed under part A comprises a volume of 5 cc., and the fluorinated hydrocarbon liquids also comprise a volume of 5 cc. under the same temperature conditions of 20 F. The fluorinated hydrocarbons represent about 50% volume per volume of the final aerosol mixture. The weight per volume percentage of the active ingredient and the ascorbyl palmitate in the final aerosol mixture are determined by dividing the listed percent figures by two.

EXAMPLE VI A. ALCOHOL SOLUTION 6 EXAMPLE VIII A. ALCOHOL SOLUTION Percent Ingredient Amount Isoproteronol Hydrochloride Ascorbyl Palmitate Distilled Water Ethyl Alcohol (200 Proof), q.s

10 B. FLUORINATED HYDROCARBONS Dichlorotetrafluoroethane (Freon 114)-.. 6.0 gms. Dichlorodifiuoromethane (Freon 12)..- 1.90 gms 15 EXAMPLE IX A. ALCOHOL SOLUTION Percent Ingredient Amount Isoproteronol Hydrochloride mg Ascorbyl Palmitate 5 mg.

Distilled Water 500 mg Ethyl Alcohol (200 Proof), q.s 5 cc.

B. FLUORlNATED HYDROOARBONS Dichlorodifluoromethane (Freon 12)-.." 7.4 gms.

EXAMPLE X A. ALCOHOL SOLUTION Percent Ingredient Amount isoproteronol Hydrochloride Ascorbyl Palmitate- Distilled Water Ethyl Alcohol (200 Pr Trichloromonofluoromethane (Freon 11) 0 Dichlorodifluorornethane (Freon 12).-.. 0.7 gms.

Others may practice the invention in any of the numerous Ways which will be suggested by this disclosure to one skilled in the art. All such practice of the invention is considered to be a part hereof provided it falls within the scope of the appended claims.

I claim:

1. A stable isoproteronol aerosol composition comprising a mixture of about equal volumes of substantially anhydrous ethanol and a liquefied fluorinated hydrocarbon characterized in having at least one fluorine atom and not more than two carbon atoms; said mixture containing therein from about 0.1 to about 0.3% isoproteronol hydrochloride and at least about 0.05% ascorbyl palmitate.

2. A stable isoproteronol aerosol composition comprising a mixture of about equal volumes of substantially anhydrous ethanol and liquefied fiuorinated hydrocarbons characterized in having at least one fluorine atom and not more than two carbon atoms; said mixture containing therein from about 0.1% to about 0.3% isoproteronol hydrochloride and at least about 0.05% ascorbyl palmitate.

3. A stable isoproteronol aerosal composition comprising a mixture of about equal volumes of anhydrous ethanol and a liquefied fluorinated hydrocarbon characterized in having at least one fluorine atom and not more than two carbon atoms; said mixture containing therein from about 0.1% to about 0.3% isoproteronol hydrochloride and at least about 0.05% ascorbyl palmitate.

4. A stable isoproteronol aerosol composition comprising a mixture of about equal volumes of anhydrous ethanol and liquefied fluorinated hydrocarbons characterized in having at least one fluorine atom and not more than Percent Ingredient Amount 0.5 Isoproteronol Hydrochloride 25 mg. 0.4 Ascorbyl Palnn'tate 20 mg.

Ethyl Alcohol (200 Proof), q.s 5 cc.

B. FLUORINATED HYDROCARBONS 90 Dichlorotctrafiuoroethane (Freon 114). 7.2 ms. 10 Dichlorodifluoromethane (Freon 12) .74 gms.

A. ALCOHOL SOLUTION Percent Ingredient Amount 0.5 Isoproteronol Hydrochloride 25 mg. 0.5 Ascorbyl Palmitate 25 mg.

Ethyl Alcohol (200Proot), q.s 5 cc.

B. FLUORINATED HYDROCARBONS 70 Dichlorotetrafluoroethane (Freon 114).-. 5.6 g'ms. 30 Dichlorodifluoromethane (Freon 12) 2.2 1115.

5. A stable isoproteronol aerosol composition comprising a mixture of about equal volumes of anhydrous ethanol and liquefied fluorinated hydrocarbons characterized in having at least one fluorine atom and not more than two carbon atoms; said mixture containing therein from about 0.1% to about 0.2% isoproteronol hydrochloride and from about 0.1% to about 0.2% ascorbyl palmitate.

6. A stable isoproteronol aerosol composition comprising a mixture of about equal volumes of substantially anhydrous ethanol and a liquefied fluorinated hydrocarbon characterized in having at least one fluorine atom and not more than two carbon atoms; said mixture containing therein about 0.25 isoproteronol hydrochloride, about 1% water and about 0.2% ascorby-l palmitate.

7. A stable isoproteronol aerosol composition comprising a, mixture of about equal volumes of substantially anhydrous ethanol and liquefied fluorinated hydrocarbons characterized in having at least one fluorine atom and not more than two carbon atoms; said mixture containing therein about 0.25% isoproteronol hydrochloride, about 1% water and about 0.2% ascorbyl palmitate.

8. A stable isoproteronol aerosol composition comprising a mixture of about equal volumes of anhydrous ethanol and a liquefied fluorinated hydrocarbon characterized in having at least one fluorine atom and not more than two carbon atoms; said mixture containing therein about 0.25% isoproteronol hydrochloride and about 0.2% ascorbyl palmitate.

9. A stable isoproteronol aerosol composition comprising a mixture of about equal volumes of anhydrous ethanol and liquefied fluorinated hydrocarbons characterized in having at least one fluorine atom and not more than two carbon atoms; said mixture containing therein about 0.25% isoproteronol hydrochloride and about 0.2% ascorbyl palmitate.

10. A composition according to claim 9' wherein the liquefied fluorinated hydrocarbons consist of a combination of about eight parts dich-lorotetrafluoroethane and about two parts dichlorodifiuoromethane.

References Cited in the file of this patent UNITED STATES PATENTS 2,350,435 Wells et al June 6, 1944 2,868,691 Porush et a1 Jan. 13, 1959 

1. A STABLE ISOPROTERNOL AEROSOL COMPOSITION COMPRISING A MIXTURE OF ABOUT EQUAL VOLUMES OF SUBSTANTIALLY ANHYDROUS ETHANOL AND A LIQUERFIED FLUORINATED HYDROCARBON CHARACTERIZED IN HAVING AT LEAST ONE FLUORINE ATOM AND NOT MORE THAN TWO CARBON ATOMS; SAID MIXTURE CONTAINING THEREIN FROM ABOUT 0.1% TO ABOUT 0.3% ISOPROTERONOL HYDROCHLORIDE AND AT LEAST ABOUT 0.05% ASCORBYL PALMITATE. 